Programmed Death Events

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Project Gilgamesh, like SENS, endorses a stochastic theory of aging – a theory that aging is primarily the result of the entropic deterioration of biological systems. The primary contender to stochastic theories of aging are the so-called programmed theories. Programmed theories of aging advance that aging is an inherent feature of biological systems – “programmed” within the genome of the organism.  These theories naturally place aging in the context of evolution – a perspective from which aging and death are often advanced as conferring fitness to species on the premise of promoting evolvability. Such theories, termed group selection or supra-individual selection, notwithstanding the controversy surrounding their relevance among evolutionary biologist, cannot be dismissed as evolutionary possibilities. It is plausible, given the time scale of the evolutionary process, that events on all levels – even life span – have been endogenized within the evolutionary framework.

The research of scientists like Vladimir Skulachev and Giacinto Libertini has proffered such spectacular cases of programmed organismal death or phenoptosis that it is worthwhile to consider aging as a possible manifestation of such death events. Phenoptosis may be classified as either acute or slow. Acute phenoptosis, characterized by rapid deterioration and accelerated death processes, is exemplified by the Pacific Salmon Oncorhyncus ssp. (which dies after spawning), the mayfly (which lacks a functional mouth in its adult form), and Saccharomyces cerevisiae (baker’s yeast) and Caenorhabditis elegans under stress. Other examples include the praying mantis (the male praying mantis ejaculates only after being decapitated by the female), the adatyllidium mite (the initial food source of the mite larvae is the body tissue of their mother) and squid (male squid die immediately after mating thus providing an abundant food source for predators that would prey on their eggs). Aging in Homo sapiens may possibly represent a case of slow phenoptosis.

The interpretation of aging in Homo sapiens as an instance of slow phenoptosis facilitates a bridging of the gap between programmed and stochastic theories of aging. It is a central hypothesis of Project Gilgamesh that the limit to life span imposed by supra-individual selection is mediated by stochastic processes permitted by sub-optimal repair and rejuvenation mechanisms. The efficacy of the repair mechanisms is selected so as to yield a specifies-specific life span. In summary, the human body ages by stochastic processes regulated by repair and rejuvenating mechanisms with an efficacy prescribed by evolutionary forces. While the validity of programmed theories of aging has been acknowledged, aging, in Homo sapiens, retains its stochastic character and the resolution of the aging problem remains a problem of error correction.    

Project Gilgamesh and SENS

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Strategies for Engineered Negligible Senescence (SENS), the brainchild of British biomedical gerontologist Aubrey de Grey, represents the most audacious initiative directed at the elimination of ageing.

The SENS program rests on the fundamental recognition of aging as resulting from damage accumulation of a various types. The program categorizes these forms of damage under seven types – the Seven Deadly Things.  These Seven Deadly Sins are identified as 1 death resistant cells, 2 cell lose without replacement, 3 genetic and epigenetic mutations, 4 mitochondrial DNA damage, 5 extracellular cross-linking 6 extracellular junk accumulation 7 intracellular junk accumulation.

Not only has the SENS program identified these Seven Deadly Things but it has tendered seven corresponding strategies for addressing these forms of damage and has – most importantly – implemented seven strands of research dedicated to the implementation of the stated strategies.    

Project Gilgamesh shares the fundamental view of SENS that aging is primarily the result of damage accumulation. Project Gilgamesh also makes recourse to aging in the evolutionary context and is informed by programmed theories of aging. The distinguishing feature of Project Gilgamesh is its approach to aging elimination as heavily reliant on molecular repair nanotechnology and the Principle of Minimal Interference. Project Gilgamesh emphasizes that developments in protein design, drug delivery and intelligent biological systems (such as DNA computing) will open up the way for more sophisticated nanotechnology. It also stresses the importance of the development of cancer nanotechnology as a starting point for the development of generic molecular repair nanotechnology.         

The Policy of Minimal Interference

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As previously discussed in Aging as Error Accumulation and Aging Elimination as Error Correction, it is instructive to view aging as error accumulation and aging elimination as of error correction. The error correction is mediated by information vectors. Information vectors may be viewed as a generic class of processes or entities which includes DNA computing and molecular repair nanotechnology. It is easy to imagine these information vectors as miniaturized robots or, generally, entities of composition and processes foreign to human physiology.

But the human body, by virtue of the host of complex mechanisms which define it, possesses intrinsic intelligence or body intelligence. The Policy of Minimum Interference (PMI) advances that in the construction of information vectors, one should exhaust body intelligence before venturing beyond. Body intelligence may be classed as either Type I or composition body intelligence, or Type II or process body intelligence.

Applying PMI with respect to Type I body intelligence requires that information vectors be constructed out of endogenous biological components  i.e. ribosomes, oligonucleotides, polypeptides, lipids etc. This application of PMI does not require conformity with process i.e. processes incorporated in information vectors may be foreign to the human body. Applying PMI with respect to Type II body intelligence does not require that information vectors meet the aforementioned composition constraint but requires adherence to the process constraint i.e. it mandates the employment of endogenous biological processes (DNA replication, transcription, translation etc.) Application of PMI may also occur with respect to both Type I and Type II body intelligence – both composition and process. It is this form of the PMI which is in effect when it is pronounced that “in the construction of information vectors, one should exhaust body intelligence before venturing beyond.”

The rationale for the PMI rests on a profound confidence in the efficacy of the evolutionary process to proffer solutions to biological problems. Nature – in the form of biological systems – represents a vast repository of ready-made solutions and it is in the interest of biomedical gerontologists to avail themselves of this boon. As a guiding policy, the PMI is also well-aligned with the biocompatibility requirement of life extending therapies and promises an added efficacy in so far as efficacy is reliant on biocompatibility.     

It must be emphasized that, in the construction of information vectors, the PMI advocates merely that one should apply the principle as far as possible; not that one should not violate the principle. In the correction of the aging problem, it is necessary that we go beyond body intelligence.

Cancer Nanomedicine as a Foundation for Molecular Repair Nanotechnology

Of the Seven Deadly Things, cancer is debatably the most formidable. This assertion is based on the genericity of cancer as indicated by its potential genesis in every cell type and its broad range of causes – chemical carcinogens, aging, lifestyle, radiation, infection, genetic constitution etc. Cancer is accordingly a focal point of life extension research. Project Gilgamesh proclaims that the development of anti-cancer medicine in the form of cancer nanomedicine represents a culmination of the three-fold requirement of augmented molecular recognition, biomimetics, and secondary intelligence (as the foundation for molecular repair nanotechnology discussed in Targeted Drug Delivery Systems as Prototypical Nanotechnology).

In Targeted Drug Delivery Systems as Prototypical Nanotechnology, the targeted drug delivery system was tendered as a prototypical foundation for molecular repair nanotechnology on the premise of its heavy reliance on molecular recognition and biomimetics. However, it generally does not make use of any sophisticated form of secondary intelligence. Cancer nanomedicine represents the targeted drug delivery system augmented by a sophisticated from of secondary intelligence. Accordingly, it represents a more appropriate basis for the development of molecular repair nanotechnology.

Present proposals for targeted drug delivery systems make use of DNA nanotechnology in the form of DNA nanostructures compatible with DNA computing, facilitating direct sensing of biochemical environment. For example, logic circuits based on nucleic acids can be potentially be used as the kernel of a drug delivery system that releases a drug in response to a well-defined stimulus (such as a specific mRNA sequence). In addition, the DNA origami method affords the synthesis of a DNA “box” with a controllable lid. Such a structure (and other related structures) could enclose a drug in its closed configuration, and open to release it in close proximity to its target in response to a specific molecular stimulus. Proof of concept studies have also demonstrated the efficacy of targeted drug delivery systems that deliver their load directly inside cells. These proposals do highlight all three of aforementioned requirements for the prototypical foundation for molecular repair nanotechnology – augmented molecular recognition, biomimesis and secondary intelligence.

A milestone in the context of sophisticated secondary intelligence is the publication, in Nature by Shapiro et al., of the construction of a DNA computer with an input and output module theoretically capable of diagnosing cancerous activity on a cell by cell basis, and releasing an anti-cancer drug upon diagnosis. Other valuable investigations have followed the work of Shapiro et al. Another noteworthy development which redounds to the infinite benefit of DNA computing and its applications is the recent invention of the transcriptor (biological analogue of the electronic transistor) by a team of bioengineers from Stanford University.               

The development of cancer nanomedicine serves the life extension agenda in two significant ways. First, it addresses the problem of cancer. Second, it serves as a foundation for the development of molecular repair nanotechnology – the single most promising technology for the eradication of all seven of the Seven Deadly Things.

Targeted Drug Delivery Systems as Prototypical Nanomedicine

It is a characteristic belief of Project Gilgamesh that the preparation of molecular repair nanotechnology may find a solid foundation in a technology which combines refined molecular recognition, molecular biomimetics and intelligent procedures (such as DNA computing). The present technology which best encapsulates this doctrine is the targeted drug delivery system.

Targeted drug delivery aims primarily to reduce the side effects and improve the efficacy of pharmaceuticals by targeting drug packages to localized sites via the specificity of ligand-ligand interactions (the drug packages may be coated with proteins that bind specifically with a single receptor or a small class of receptors). This fulfills the refined molecular recognition requirement (which can be achieved through protein design).

The biomimetic requirement is naturally met by the high premium placed by pharmacology on the biocompatibility of drug delivery systems and the present emphasis on drug delivery vehicles inspired by biochemistry – polymeric micelles, liposomes, dendrimers and artificial DNA nanostructures. The rationale for biomimetics will be fully expressed in The Policy of Minimal Interference.     

A targeted drug delivery system premised on augmented molecular recognition and biomimetics is compatible with a high level of efficacy. Nevertheless, the exigencies of further reduction of side-effects and improved efficacy – especially in the context of cancer treatment – calls for a body intelligence more sophisticated than that inherent in augmented molecular recognition. The targeted drug delivery system, imbued with a secondary intelligence (in the form of DNA computing etc.), thus becomes the prototype for molecular repair nanotechnology. The modalities of these secondary intelligences shall be considered in the next post, Cancer Nanomedicine as a Foundation for Molecular Repair Nanotechnology.             

Beyond Body Intelligence: Molecular Repair Nanotechnology

As previously established in Body Intelligence, body intelligence is not compatible with aging elimination (in Homo sapiens, for spectacular results have been achieved in the so-called negligibly senescent organisms such as T. dohrnii). The repair capabilities of the human body are simply too limited. This limitation may be considered in an evolutionary context. From this perspective, an indefinite life span for Homo sapiens may be construed as unfavorable to the evolvability of the species or the result of “evolutionary negligence”, pleiotropic effects or energy tradeoffs as expressed by the seminal theories of Medawar, Williams (antagonistic pleiotropy) and Kirkwood (disposable soma theory), respectively. However, though the curtailing of longevity (on the premise of its deleterious effect on evolvability) may have been exigent in evolutionary prehistory, it may no longer be functional. Present day life spans for Homo sapiens may simply represent a vestige of an ancient requirement – merely a single solution to the evolutionary problem of the propagation of the species. It is not untenable that there are other viable solutions that translate to protracted life spans but that these solutions are “kinetically” separated from the present solution and require an “activation energy” (which may be provided by life extension). Alternatively, it may be argued that the evolutionary procedure has found a satisfactory solution to the problem of gene propagation and evolvability and consequently has no incentive for “finding” another strategy which may be just as good (or better).

Whatever the obstacles standing in the way of the life extension, it is indisputable that we need to go beyond body intelligence. This necessitates the use of external agents (information vectors) such as molecular repair nanotechnology. Molecular repair nanotechnology may ultimately form the basis of the transformation of human biochemistry via their seamless integration into the human physiology (a prospect most likely to be realized through synthetic biology, genetic engineering and nanomedicine).   

Molecular Recognition as the Most Fundamental Kind of Body Intelligence

Body Intelligence constitutes the complexity of the physiological processes which underlie the operation of a biological system. Most of these processes are dominated by mechanisms that are highly reliant on molecular recognition (the ability of one molecule to bind stably and specifically with another). Molecular recognition interactions may generally be termed ligand-ligand interactions and include all enzyme-substrate reactions, antibody-antigen reactions, as well as the interactions of hormones and neurotransmitters with their receptors. 

It is impossible to identify a physiological event of reasonable complexity which does not owe this complexity – most fundamentally – to molecular recognition. This renders molecular recognition the most fundamental kind of body intelligence. Furthermore, since most molecular recognition events involve either protein-protein or protein-non-protein interactions, a refined understanding of the structure of proteins is of prime importance in augmenting the body Intelligence afforded by molecular recognition.

Accordingly, Project Gilgamesh recognizes the supreme value of protein design to life extension and sees it as the most basic means of augmenting the intelligence of physiological processes by refining the specificity of ligand-ligand interaction of newly engineered biological processes and modulating the affinity of such interactions, through custom-designed proteins.

The fundamental problem of protein design is the determination of primary structure of a protein from its tertiary structure. This problem should not be confused with protein structure prediction – the reverse problem of determining the tertiary structure of a protein from its primary structure.

Body Intelligence

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It is traditional to render intelligence the prerogative of higher life forms and to strictly deny it to simpler forms such as bacteria and unicellular eukaryotes. But such a categorization is predicated on little else but a convenient dualism. It seems more proper to perceive intelligence as a property present in any system to the extent of the structural and functional complexity of that system. Such a redefinition renders intelligence a property distributed among systems, not according to kind, but according to degree.

The human body represents a multiplicity of highly structured physiological processes. This constitutes the body intelligence of the human body. Notable examples of body Intelligence include the processes of DNA replication, transcription and translation, DNA repair, signal transduction, gene regulation, electron transport, and oxidative phosphorylation

Nucleotide repair processes represent one of many examples of body Intelligence in the capacity of repair. Since repair is fundamental to addressing the aging problem, the intrinsic repair capabilities of the human body represent a partial solution to the aging problem. The limitations of the repair processes are inherent and not without value. Beyond the inexorable error issuing from the entropy law of thermodynamics, the error rate of a physiological process such as DNA replication may represent the result of a tradeoff between error rate and metabolic rate. The enzymes and other DNA replication apparatus may simply be incapable of meeting the demands of a lower error rate without compromising speed. Also, errors in the form of mutations are the fodder of the evolutionary process and consequently play a pivotal functional role. Furthermore, it is impossible for a biological system to function without some degree of error as the error-correcting mechanisms are themselves susceptible to error. These intrinsic limitations can only be ameliorated by the external injection of information (mediated by information vectors), or the reengineering of the human body (under the guidance of such disciplines as synthetic biology).

Body intelligence (in the form of repair processes), though it tenders a partial solution, is unsatisfactorily limited. Aging elimination therefore mandates that we venture beyond body intelligence.         

Intelligence and Information Vectors

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The theory of aging advanced under Project Gilgamesh and shared by the SENS program is that aging is stochastic – characterized by the accumulation of small random errors in biological systems over time. The accumulation of errors is inexorable and a manifestation of a fundamental law of physics – the law of entropy. The law of entropy states that given sufficient time all closed systems attain equilibrium – an informational state characterized by maximum randomness. This law is often put forward as the basis of the infeasibility of aging elimination and the realization of life extension. However, the proclamation of the infeasibility of life extension on such a premise epitomizes the dangers of a little knowledge for evidently a biological system is not a closed system. As such, the law of entropy does not present an obstacle to life extension for it is also a fundamental principle of physics that the entropic decay of a system may be counteracted by the injection of energy into that system.

We have proclaimed that what is needed to counteract the entropic degradation of biological systems (the underlying cause of aging) is the injection of energy into that system. But energy is only a necessary requirement, not a sufficient one. Innumerable instances of energy injection not accompanied by a reversal of entropic degradation may be readily conceived, with the cremation of an individual representing an extreme case. Under crematory conditions, energy injection certainly occurs but only expedites the entropic decay – an effect contrary to the supposition that energy injection is a necessary and sufficient criterion for the counteraction of entropic deterioration in a biological system. If mere energy is deficient in the resolution of the aging problem, then to which concept must we turn?

In What is Life? (1944), Nobel Prize-winning theoretical physicist Erwin Schrodinger tendered the concept of negative entropy as the physical quantity imported by a biological system to counteract the deteriorative effects of entropy. The term was later shortened to negentropy by Léon Brillouin. Negentropy is an insightful concept which transcends the energy concept and permits us to more appropriately formulate the procedure by which aging elimination may be attained. Contrary to the importation of energy which may or may not expedite entropic deterioration, the importation of negentropy is always accompanied by the attenuation of entropy.

This, however, implies that the unlimited importation of negentropy eventually results in a biological system characterized by zero entropy. At zero entropy, the use of the term “biological system” is really a misnomer for a “system” of such high order is necessarily devoid of functionality. This represents a fundamental limitation of the negentropy concept. A Further limitation is that a given entropy level may correlate with a variety of biological states which represent various degrees of health and even death. Knowledge of the entropy of a healthy biological state does not translate to knowledge of the pattern of atoms or atomic interaction which defines the healthy state (owing to the lack of a one-to-one mapping between the configuration of a biological state and its entropy). The negentropy measure, though more utile, must join the energy concept in the realm of defectiveness for neither concept adequately captures the idea of restoring the body to healthy biological states.

To summarize, the necessary and sufficient condition for the restoration of a healthy state is not energy which is generic in the sense that it permits activity but does not delimit on the type of activity permitted. It is not negentropy as it is intuitive that any system requires some minimal entropy to function and that the unbridled activity of negentropy will result in a body state that is too ordered to be alive.

If the concept of negentropy also fails, then what ensures the restoration of a healthy state? The thing which has to be restored is, somewhat anti-climactically, the precise information content of the healthy state i.e. the configuration of the healthy state. This certainly does not mean that such a state is singular but that it has a low degree of freedom in relation to the totality of unhealthy states. Any external intelligence which attempts to restore the configuration of the healthy state must necessarily possess access to the information content of that configuration (an information type which is highly compressible).

The restoration of the configuration of the healthy state transcends the energy and negentropy criteria. It requires not merely the expenditure of energy and the attenuation of entropy but the expenditure of energy in such a way that it is not only entropy-reducing but information-restoring.

The restoration of the healthy state is thus an exercise in intelligence by entities which may be generally termed information vectors (borrowing a term from João Pedro de Magalhães). This intelligence is only partially possessed by the body since if it was possessed in entirety, aging would have been nonexistent. Although the body does possess inherent intelligence as characterized by the definability and functionality of its innumerable physiological processes, it just does not possess the quality of intelligence which translates to a permanent healthy state. For this reason, the body requires a modification which must necessarily take the form of external intelligent agents or information vectors such as molecular repair nanotechnology.

It is conceivable that the status of information vectors as external agents may only be temporary and that they will eventually be seamlessly integrated into biological processes as inheritable phenotypes – a prospect which is not beyond the ambit of the emerging field of synthetic biology.

Aging Elimination as Error Correction

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If aging is construed as a problem of error accumulation, then aging elimination is necessarily a problem of error correction. The errors which constitute aging have been established under the SENS program as the seven in number – namely death resistant cells, cell death without replacement, genetic and epigenetic mutation, mitochondrial DNA damage, extracellular cross-links, extracellular junk accumulation and intracellular junk accumulation.

The strategies for the repair of these types of damage involve removal, replacement (facilitated by such technologies as stem cell therapy, tissue engineering and organ transplantation) and/or repair. All of these strategies require – for their most efficacious implementations – a fine level of manipulation in the form of nanotechnology of some kind. In the case of the brain – the seat of identity – repair as opposed to replacement technology seems indispensable (though this does not rule out the utility of gradual removal and replacement). Aging elimination in its most potent form seems ultimately to require recourse to error correction. The prospect of mind uploading, though it cannot be dismissed as a possibility, seems to require the solution of problems which are beyond the physics and chemistry of correction (such as philosophical problems of identity and whether or not consciousness is substrate-dependent).

The feasibility of aging elimination as an issue of error correction is not hindered by any known law of physics (and it is inconceivable that it may be so hindered by the unknown). All seven errors of the SENS program resolve – on the finest scale – into undesirable chemical reactions. The correction of such error therefore translates to the reversal of these chemical reactions. The laws of chemical thermodynamics permits that all chemical reactions may be reversed under the singular requirement that the necessary energy be supplied for the reversal.

This is the fundamental argument for the feasibility of error correction in a biological system and consequently the fundamental argument for the attainability of aging elimination and the realization of radical life extension.